The behavioral effects of alcohol have long been considered to depend on gamma-amino-butyric acid (GABA) neurotransmission. Recently, the GABAA receptor isoform, 1424, has been proposed to mediate effects of alcohol at low-to-moderate concentrations. The current proposal will examine this possibility by testing the hypothesis that the 1424 GABAA receptor mediates aspects of the reinforcing properties of ethanol, thereby critically contributing to voluntary intake of ethanol. We will use viral-mediated RNA interference to knock down expression of the 14 and 4 GABAA receptor subunits in the nucleus accumbens, a brain region involved in processes of reward and reinforcement, to probe the contribution of the 1424 GABAA receptor to ethanol drinking behaviors by rats. Within our experimental aims we will test the contribution of this receptor to oral ethanol consumption, as well as to instrumental responding for ethanol. We will also initiate studies of the mechanism whereby ethanol in the NAc interacts with the 1424 GABAA receptor, using in vitro electrophysiogical techniques. Together, these studies will serve to define a role for two unique subunits of the GABAAR in a primary region of the brain reward circuitry, the NAc, in the reinforcing effects of ethanol. Understanding the neural mechanisms that mediate ethanol's reinforcing effects is critical for the development of treatments to assist in pharmacological therapies for alcohol abuse and alcoholism. PUBLIC HEALTH RELEVANCE The elucidation of the neurotransmitter and receptor systems that support alcohol drinking is critical for understanding how the pharmacological actions of alcohol lead to voluntary intake of alcohol, including under conditions of abuse. If the GABAA receptor studied in the experiments in this proposal is found to contribute to alcohol drinking, then future research on possible pharmaceutical approaches to reduce drinking by interacting with this receptor would be indicated. [unreadable] [unreadable] [unreadable]